Paolini Erika, Longo Miriam, Meroni Marica, Tria Giada, Cespiati Annalisa, Lombardi Rosa, Badiali Sara, Maggioni Marco, Fracanzani Anna Ludovica, Dongiovanni Paola
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy.
Front Nutr. 2023 Mar 2;10:1101341. doi: 10.3389/fnut.2023.1101341. eCollection 2023.
The PNPLA3 p.I148M impact on fat accumulation can be modulated by nutrients. Niacin (Vitamin B3) reduced triglycerides synthesis in and NAFLD models.
In this study, we aimed to investigate the niacin-I148M polymorphism crosstalk in NAFLD patients and examine niacin's beneficial effect in reducing fat by exploiting hepatoma cells with different genotype.
We enrolled 172 (Discovery cohort) and 358 (Validation cohort) patients with non-invasive and histological diagnosis of NAFLD, respectively. Dietary niacin was collected from food diary, while its serum levels were quantified by ELISA. Hepatic expression of genes related to NAD metabolism was evaluated by RNAseq in bariatric NAFLD patients ( = 183; Transcriptomic cohort). Hep3B (148I/I) and HepG2 (148M/M) cells were silenced (siHep3B) or overexpressed (HepG2 ) for , respectively.
In the Discovery cohort, dietary niacin was significantly reduced in patients with steatosis ≥ 2 and in I148M carriers. Serum niacin was lower in subjects carrying the G at risk allele and negatively correlated with obesity. The latter result was confirmed in the Validation cohort. At multivariate analysis, the I148M polymorphism was independently associated with serum niacin, supporting that it may be directly involved in the modulation of its availability. siHep3B cells showed an impaired NAD biosynthesis comparable to HepG2 cells which led to lower niacin efficacy in clearing fat, supporting a required functional protein to guarantee its effectiveness. Conversely, the restoration of PNPLA3 Wt protein in HepG2 cells recovered the NAD pathway and improved niacin efficacy. Finally, niacin inhibited through the ERK1/2/AMPK/SIRT1 pathway, with the consequent -driven reduction only in Hep3B and HepG2 cells.
We demonstrated a niacin-PNPLA3 I148M interaction in NAFLD patients which possibly pave the way to vitamin B3 supplementation in those with a predisposing genetic background.
PNPLA3 p.I148M对脂肪堆积的影响可受营养素调节。烟酸（维生素B3）在[具体模型1]和[具体模型2]非酒精性脂肪性肝病（NAFLD）模型中可减少甘油三酯合成。
在本研究中，我们旨在调查NAFLD患者中烟酸 - I148M多态性的相互作用，并通过利用具有不同[具体基因型]的肝癌细胞来研究烟酸在减少脂肪方面的有益作用。
我们分别纳入了172例（发现队列）和358例（验证队列）经非侵入性和组织学诊断为NAFLD的患者。从食物日记中收集膳食烟酸，同时通过酶联免疫吸附测定（ELISA）对其血清水平进行定量。通过RNA测序评估肥胖型NAFLD患者（n = 183；转录组队列）中与烟酰胺腺嘌呤二核苷酸（NAD）代谢相关基因的肝脏表达。分别对Hep3B（148I/I）和HepG2（148M/M）细胞进行沉默（siHep3B）或过表达（HepG2[具体处理方式]）处理。
在发现队列中，脂肪变性≥2级的患者和I148M携带者的膳食烟酸显著减少。携带风险等位基因G的受试者血清烟酸较低，且与肥胖呈负相关。在验证队列中证实了后一结果。在多变量分析中，I148M多态性与血清烟酸独立相关，支持其可能直接参与调节其可用性。siHep3B细胞显示出与HepG2细胞相当的NAD生物合成受损，导致烟酸清除脂肪的功效降低，这支持了需要功能性蛋白来保证其有效性。相反，在HepG2细胞中恢复PNPLA3野生型蛋白可恢复NAD途径并提高烟酸功效。最后，烟酸通过细胞外调节蛋白激酶1/2/腺苷酸活化蛋白激酶/沉默信息调节因子1（ERK1/2/AMPK/SIRT1）途径抑制[具体物质]，结果仅在Hep3B和HepG2细胞中由[具体物质]驱动的[具体物质]减少。
我们在NAFLD患者中证明了烟酸 - PNPLA3 I148M相互作用，这可能为具有易感遗传背景的患者补充维生素B3铺平道路。
